Method of maintaining oral health in animals

ABSTRACT

Use of a compound having the formula (I) in the manufacture of a medicament for the prevention or treatment of a disease caused by oral bacteria in an animal wherein R1 is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R2 is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position, or a pharmaceutically acceptable salt thereof. A cosmetic method of preventing or decreasing oral staining in an animal, comprising the step of exposing the oral cavity to a morpholino compound of general

FIELD OF THE INVENTION

The present invention relates to the maintenance of oral health inanimals.

BACKGROUND OF THE INVENTION

The need to maintain good oral health in humans has been recognised fora very long time. However, it is only recently that significant advancesin maintaining the oral health of animals have been made. In particular,there has been a rapid increase in the number of academic publicationsin the field of veterinary dentistry in the last 20 years; the Academyof Veterinary Dentistry and the American Veterinary Dental College wereestablished in 1987 (Easley, J Hist Dent: Vol. 47, No. 2, July 1099 pp83-85).

Veterinary oral health products and treatments are a rapidly growingmulti-million pound industry, in particular in the pet, or “companionanimal”, sector. US retail sales in this sector are estimated to begreater than US$400m per year.

Animals are susceptible to the majority, if not all, of the adverse oralhealth conditions that affect humans, including the formation of plaqueand tartar (calculus), gingivitis, periodontitis, unsightly dentalstaining and halitosis. Methods and products are required to prevent andtreat all of these conditions. It is particularly important to maintainoral health in animals because the range of corrective measures that areavailable to humans, such as dentures and complex dental surgery, arenot readily available for animals.

Delmopinol is a morpholino compound that has utility in the removal orinhibition of dental plaque in humans. The compound and its manufactureare disclosed in U.S. Pat. No. 4,894,221.

SUMMARY OF THE INVENTION

The present Invention is based on the surprising finding that acomposition comprising Delmopinol (or a derivative or salt thereof) iseffective in maintaining the oral health of animals, in particularcompanion animals.

According to a first aspect of the invention, a compound having theformula (I) is used in the manufacture of a medicament for theprevention or treatment of a disease caused by oral bacteria in ananimal, wherein R₁ is a straight or branched alkyl group containing 8 to16 carbon atoms at the 2- or 3-position of the morpholino ring, and R₂is a straight or branched alkyl group containing 2 to 10 carbon atoms,substituted with a hydroxy group except in the alpha-position, or apharmaceutically acceptable salt thereof.

According to a second aspect of the invention, a cosmetic method ofpreventing or decreasing oral staining in an animal comprises the stepof exposing the oral cavity to a morpholino compound of general formula(I).

According to a third aspect of the invention, an animal chew comprises acompound of formula (I) or a medicament comprising the compound offormula (I).

According to a fourth aspect of the invention, an animal foodstuffcomprises a compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

A morpholino compound of formula (I) is effective in maintaining thehealth and favourable aesthetics of an animal's oral cavity. Amorpholino compound according to the invention has the general formula(I)

wherein R₁ is a straight or branched alkyl group containing 8 to 16carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is astraight or branched alkyl group containing 2 to 10 carbon atoms,substituted with a hydroxy group except in the alpha-position, orpharmaceutically acceptable salts thereof. In a preferred embodiment,the sum of the carbon atoms in the groups R₁ and R₂ of the morpholinocompound is at least 10, preferably between 10 and 20. In a furtherpreferred embodiment, the R₂ group terminates with the hydroxy group.

The claimed morpholino compounds are known per se and can bemanufactured by any known method, for example that disclosed in U.S.Pat. No. 5,082,653 and WO90/14342, which are incorporated herein byreference.

The preferred morpholino compound for use in the invention is3-(4-propyl-heptyl)-4-(2-hydroxyethyl)morpholine, which is commonlyknown as Delmopinol (CAS No. 79874-76-43).

The morpholino compounds can be used in their free base form or as apharmaceutically acceptable salt thereof. Examples of pharmaceuticallyacceptable salts are the salts of acids such as acetic acid, phosphoricacid, boric acid, hydrochloric acid, maleic acid, benzoic acid, citricacid, malic acid, oxalic acid, tartaric acid, succinic acid, glutaricacid, genistic acid, valeric acid, gallic acid, beta-resorcyclic acid,acetyl salicylic acid, salicylic acid, perchloric acid, barbituric acid,sulfanilic acid, phytic acid, p-nitro benzoic acid, stearic acid,palmitic acid, oleic acid, myristic acid, lauric acid and the like. Themost preferred salts are those of hydrochloric acid. A preferredcompounds is delmopinol hydrochloride (CAS No. 98092-92-3).

The morpholino compounds are useful in preventing and treating diseasescaused by oral bacteria in an “animal”. As used herein, the term“animal” is to be given its recognised meaning in the art, i.e. anynon-human member of the animal kingdom. Preferably, the animal is anon-human mammal.

In a preferred embodiment, the animal is a “companion animal”. As usedherein, the term “companion animal” refers to an animal that is kept asa “pet” by a person for companionship and enjoyment. These will usuallybe mammals such as cats, dogs, rabbits, ferrets and rodents. The mostpreferred companion animals are cats and dogs.

In an alternative embodiment, the animal is “livestock”, i.e. an animalthat is reared agriculturally to provide a useful product. A livestockanimal is usually a mammal, including but not limited to pigs, cows,goats, donkeys, sheep and llamas.

In another alternative embodiment, the animal is a “performance animal”such as a racehorse or racing greyhound. The skilled person willrecognise the need for these animals to be maintained in optimum health,including oral health.

The morpholino compounds have been found to be particularly effective inmaintaining the health and favourable aesthetics of an animal's oralcavity. The morpholino compounds have several medical (i.e. veterinary)applications, as follows: prevent and remove plaque and calculusformation in the oral cavity, particularly on the teeth; prevent andtreat gum diseases including gingivitis and periodontitis; and preventand treat halitosis. They also have a cosmetic application, as they areable to remove stains from, or “whiten”, the teeth.

A morpholino compound of formula (I) may be incorporated into amedicament, composition or formulation. When a morpholino compoundaccording to the invention is manufactured as a medicament, the skilledperson will realise that the morpholino compound of formula (I) may bethe only active ingredient in the final medicament. However, the finalmedicament may contain other pharmaceutically acceptable ingredients,both inert (i.e. an “excipient”) and pharmaceutically active. Anycombination of a compound of formula (I) and one or more of thepharmaceutically acceptable ingredients disclosed below is within thescope of the invention. When the compound of formula (I) is prepared asa cosmetic, excipients may be added, which will be apparent to oneskilled in the art.

The compound of formula (I) may be administered to an animal incombination with at least one anti-microbial, preferably anti-bacterial,agent. Suitable agents include the antibiotics tetracycline, doxycylineand ampicillin and the anti-bacterial agents triclosan (2,4,4′-trichloro2′-hyrdoxy diphenyl ether) and Chlorhexidine digluconate(1,1′-hexamethylene-bis[(5-p-clorophenyl)-biguanide]).

The compound of formula (I) is useful in treating and preventing gumdisease and associated inflammation of the gums. The compound of formula(I) may be administered to an animal in combination with at least oneanti-inflammatory agent. Anti-inflammatory agents are well known in theart and any may be used. Preferably, the anti-inflammatory agent is anon-steroidal anti-inflammatory drug (NSAID), such as aspirin(acetylsalicylic acid) or ibuprofen. In an alternative embodiment, asteroidal anti-inflammatory agent, for example cortisone, may be used.

The compound of formula (I) can be added to toothpaste, dentifrice, gum,gel or mouthwash formulations. The concentration of the morpholinocompound of formula (I) that is required will vary depending on theanimal to be treated and the nature of the formation, as will beapparent to the skilled person. An example of a suitable concentrationof the preferred compound, delmopinol, is 0.2% w/v.

In a preferred embodiment, the compound is present in an animal chew. Asused herein, the term “chew” is given its normal meaning in the art andrefers to any toy, accessory or foodstuff that is intended for chewingor gnawing by an animal. The skilled person will recognise that suitable“chew” size and composition will vary depending on the animal. Chews maybe made from animal products such as hide (animal skin), tendon or bone,man-made products such as plastics (e.g. nylon) and man-made rubber, andplant products such as natural rubber. Other suitable materials formaking a chew will be apparent to the skilled person. A combination ofmaterials may be used. Preferably, the chew provides sufficientresistance to the chewing action of an animal that pressure is put onthe animal's teeth. It also acts to remove debris, plaque and/orcalculus by friction.

The chew may be in any shape, for example, a chew made for a cat may bein the shape of a mouse and a chew for a dog may be in the shape of abone. Preferably, the chew is shaped so that the teeth, gums end tongueare rubbed or massaged by the chew as the animal chews it, for examplethe chew may have a surface containing bumps, nodules or ridges. Thiswill aid plaque removal.

In a preferred embodiment, a compound of formula (I) is infused into thechew, i.e. the chew material contains the compound of formula (I) andreleases it over a sustained period. An example of a method of infusinga chew is to soak hide in a compound of formula (I) and then allow it todry. In an alternative embodiment, the chew is simply coated with acompound of formula (I). The chew may be flavoured with a flavouringthat is appealing to the animal it is designed for. As an example, a dogchew may be flavoured with meat flavours, such as chicken or beef.

The compound of formula (I) may alternatively be incorporated into afoodstuff that does not resist the chewing or gnawing action of ananimal i.e. foodstuffs that are readily broken down by the chewing orgnawing action. Preferred examples of such foodstuffs include animalfeeds (both wet and dry), more preferably animal biscuits. The compoundof formula (I) can be incorporated into, or coated onto the surface of,such foodstuffs. The compound of formula (I) could also be added to theanimal's usual feed.

The chew or foodstuff comprising a compound of formula (I) canadditionally comprise any of the other medicament Ingredients disclosedherein, in any combination. For example, an animal foodstuff or chew cancontain a compound of formula (I) and one or more active or inertpharmaceutical ingredients, such as an antimicrobial agent or ananti-inflammatory agent.

A single type of morpholino compound, or a number of different compoundsmay be present in the composition, medicament or formulation. When anumber of compounds are present, it is preferred that delmopinol is themajor morpholino compound.

In one embodiment, a compound of formula (I) is used to remove orprevent plaque formation in the oral cavity, preferably the teeth andgums of an animal, Prevention of plaque formation will prevent theformation of tartar (calculus), which forms when plaque calcifies andhardens. The terms “plaque” sod “calculus” are given their normalmeaning in the art. For the avoidance of doubt, plaque is abacteria-based film that can occur on oral surfaces. Calculus (alsoknown as tartar) is a hardened deposit that can fom when plaque is notremoved. The two major forms of gum disease, gingivitis andperiodontitis, result from bacterial plaque formation in the oralcavity, in particular on the teeth and gums. Although long considered tobe a localised infection only, gum disease is now being investigated asa potential risk factor for the development of other, potentially moreserious, diseases including cardiovascular disease and pulmonarydisorders. Therefore, compounds of the formula (I) can be used to treat(by removing plaque) and prevent (toy preventing plaque formation) gumdiseases such as gingivitis and periodontitis. In a preferredembodiment, the gum disease has symptoms including infected sub-gingivalpockets. More preferably, the infected sub-gingival pockets are at least4 mm deep, measured from the tip of the gum line to the apex of thepocket.

A morpholino compound of formula (I) can be used to treat and preventhalitosis. As used herein, the term “halitosis” refers to the commonlyrecognised meaning of the term, i.e. “bad breath”. This may be definedas breath that has an odour that is unpleasant or offensive to theanimal exhaling the breath, or more likely to people near the animalsuch as the owner. In a preferred embodiment, the breath containsVolatile Sulphur Compounds (VSC's), including but not limited tohydrogen sulphide, methyl mercaptan or dimethylsuphide, or compoundssuch as putrescine, cadaverine, butyric and propionic acids. Thesecompounds result from proteolytic degradation of varioussulphur-containing substrates in food debris, saliva, blood andepithelial cells, by predominantly anaerobic Gram-negativemicroorganisms in the oral cavity. A compound of formula (I) can reducethe level of these compounds emitted from an animal's mouth.

A composition comprising a compound of formula (I) can be used purelycosmetically, to reduce and prevent staining in the oral cavity. Inparticular, a compound of formula (I) can whiten the teeth. Anycombination of a compound of formula (I) and one or more excipients, asdescribed herein, is within the scope of this embodiment.

As used herein, the term “oral staining” refers to any unsightlydiscolouration of the oral cavity. In particular, it refers to stainingof the teeth and tongue. The staining that is prevented and/or removedby a compound of formula (I) is caused by staining agents affecting thesurfaces of the oral cavity, preferably the surface of the tongue andteeth, most preferably the surfaces of the teeth that are visible toothers. This is commonly referred to as “extrinsic staining”.

The staining can be caused by any staining agent. Animal feed can causedental staining, referred to herein as “dietary” staining agents. Theanti-bacterial agent Chlorhexidine, which is used to treat oralinfections in animals, also causes staining of the teeth. Compounds ofthe formula (I) can remove stains caused by these agents (amongstothers), and prevent further staining.

It should be understood that the term “oral staining” includes stainingof teeth, i.e. dental staining. The compound of formula (I) cantherefore be used to prevent and remove dental staining. The removal of(dark) stains from the teeth, to give them a “whiter” appearance, isreferred to herein as “whitening” of the teeth. In a preferredembodiment, the compound of formula (I) is added simultaneously orsequentially with an additional de-staining agent. This additional agentpreferably comprises a peroxide-containing whitener or bleaching agent.The combination of a compound of formula (I) and another agent that isknown to remove/prevent staining demonstrates a surprising synergy thatallows stains to be removed, i.e. teeth to be whitened, more effectivelythan when each of the agents is used separately. Alternatively, thecompound of formula (I) is the only active de-staining ingredient in thepreparation with which the oral cavity is contacted.

For all embodiments described herein, the oral cavity is exposed to(i.e. brought into contact with) a compound of formula (I). The compoundof formula (I) is brought, into contact with the oral cavity in aconventional way, in any suitable form or amount that achieves thedesired effect in the oral cavity, i.e, the reduction or prevention ofplaque formation, prevention or treatment of gum diseases includinggingivitis and periodontitis including treatment of infectedsub-gingival pockets; prevention or treatment of halitosis or teethwhitening.

Preferably, the compound of formula (I) is in the form of an aqueousmouthwash, toothpaste, gel, gum, dentifrice or other similar preparationthat will be apparent to the skilled person. In an equally preferableembodiment, the compound of formula (I) contacts the oral cavity via itspresence on or in a chew or foodstuff, as detailed above. Preferably,the compound, in whichever form is suitable, is held in the mouth for atleast 5 seconds, preferably greater than 10 seconds, for example oneminute or more. In a preferred embodiment, mechanical agitation,preferably brushing or scraping the teeth, tongue or gums, is performedsimultaneously with or shortly, preferably immediately, after contactingthe oral cavity with a compound of formula (I). However, mechanicalagitation is not required for the compounds of formula (I) to heeffective in maintaining the health and favorable aesthetics of ananimal's oral cavity. Simple contact of the oral cavity with a compoundof formula (I) is sufficient for the benefits described herein to beobtained. In one embodiment, the compound of formula (I) is applied asan aqueous mouthwash at the start of any regular (e.g. daily) oralhealth routine, such as before brushing the teeth. In a preferredembodiment, the mouthwash is applied as a spray or mist, for example anaerosol spray, or as droplets from a dropper bottle. In a furtherpreferred embodiment, the oral cavity is contacted with a compound offormula (I) shortly, preferably immediately, before contacting the oralcavity with a further agent that is helpful in maintaining good oralconditions, for example a further de-staining agent, as described above.

A method for treating (veterinary or cosmetically) any of the oralhealth conditions disclosed herein comprises contacting the oral cavityof an animal that displays symptoms of one or more of the conditionswith a compound of formula (I), preferably a preparation, composition orformulation containing a compound of formula (I) such as a toothpaste,gum, gel, dentifrice, mouthwash formulation, chew or foodstuff.Halitosis, plaque formation, calculus and gum disease can be preventedby contacting the oral cavity with a compound of formula (I), preferablya preparation containing a compound of formula (I) such as a toothpaste,gum, gel, mouthwash formulation, chew or foodstuff, prior to thedevelopment of offensive odours, plaque, calculus or disease.

The invention is further described by the following non-limitingexample.

EXAMPLE

A study was carried out to investigate the effect of dog snackscontaining delmopinol on gingivitis and calculus formation in beagledogs.

Materials and Methods

Eight female dogs were used in the study. The animals were two years oldand each weighed approximately 20 kilos. The dogs were divided randomlyinto two groups of four. The experimental group received a daily dogsnack containing delmopinol, while the control group received a dailydog snack without delmopinol.

During a pre-experimental period of four weeks, the teeth in the upperjaws of all dogs were scaled and polished professionally with a rubbercup, pumice and water, on a weekly basis. The teeth of the upper jawswere also thoroughly brushed with a toothbrush and water, for 2 minutesdaily. The teeth in the lower jaws were not cleaned. During thispre-experimental period the dogs were fed a soft gingivitis-inducingdiet. Using these procedures, two different clinical conditionsprevailed in the dogs at the end of the pre-experimental period: in theupper jaw the gingiva was clinically healthy while in the lower jawsgingivitis prevailed.

Commercially available dog snacks (pieces of cow/pig hides approximately12-15 cm long and with a diameter of around 1.5 cm) were soaked indelmopinol 10 mg/ml overnight and then dried. The experimental dogereceived a portion of the delmopinol dog snack daily in the afternoonfrom day 0 until day 14 of the experimental period. The control dogsreceived an equal amount of dog snack without delmopinol during thecorresponding period. Between days 0 to 28 of the experiment the dogswere fed a soft plaque and calculus-promoting diet only.

In the upper jaws, the presence of plaque and gingivitis was measured atthe buccal surfaces of canines, first, second, third, fourth premolarsand first molars. In the lower jaws the measurements were undertaken atthe buccal surfaces of canines and first molars, in total 18 surfaceswere examined clinically. 12 surfaces were clinically healthy prior tothe experimental period and 4 surfaces were not maintained with oralhygiene measures.

All experimental procedures, (except the tooth brushing during thepre-experimental period) were performed with the dogs anaesthetized byintravenous Pentothal (Abbot, Belgium).

The experimental procedures and measurements were blinded and theexaminer did not know which group the animals belonged to. The variousmeasurements were taken on days 0, 14 and 28. Clinical photos were takenof the upper jaws at the same occasions as the measurements.

Parameters

The presence of plaque was scored following staining of the teeth witherythrosine dye. Plaque was noted if stained dental plaque was incontact with the buccal gingival margin.

Bleeding on probing was scored according to Löe, H and Silness, J (1963)Periodontal disease in pregnancy. Prevalence and severity. ActaOdontologica Scandinavia 21, 533-551. Presence of gingivitis wasregistered if bleeding occurred within 20 seconds following gentleprobing of the buccal gingival margin.

Presence or absence of calculus was noted on the buccal surfaces of theteeth in the upper jaws.

RESULTS

The delmopinol-containing dog snack was well tolerated by the dogs. Noremains of the dog snacks were found in the dog cages showing that thedogs had consumed all the dog snacks provided.

Dental Plaque

On day 0 the teeth in the upper jaws of all dogs were plaque free due tothe polishing of the teeth. On day 14 all teeth in the control groupharboured dental plaque while the experimental group showed a reductionor around 20% in the presence of dental plaque relative the controldogs. On day 28 all teeth in both groups demonstrated dental plaque (seeTable 1).

Bleeding on Probing

On day 0 only one site in each of the experimental and control groupsshowed bleeding on probing in the previously well-maintained (healthy)maxillary (upper jaw) quadrants. On day 14, 13 of the 48 measuredmaxillary teeth/gingival units in the experimental group had bleeding onprobing while the corresponding value for the control group was 36/48.

In the experimental dogs, 15 of the 16 sites at the previously notmaintained lower jaw teeth demonstrated bleeding on probing on day 0. Onday 14 the bleeding at these teeth was reduced to five sites. On day 28bleeding on probing had increased to 21/48 sites at the upper jaw teethand to 12/16 at the lower jaw teeth. In the control group, one site inthe upper jaw and all 16 sites at the lower jaw teeth on day 0 showedbleeding on probing. On day 14 In the control group 36/48 sites in theupper jaw had bleeding on probing while at the lower jaw teeth thebleeding on probing was reduced to 8. On day 28 bleeding on probing hadincreased to 26/48 sites at the upper jaw teeth and to 14/16 sites atthe lower jaw teeth (see Table 2).

Calculus Formation

None of the of the teeth in the experimental and control group hadcalculus on day 0 because prior to the experimental start all calculuswas professionally removed. On day 14 in total 6/48 maxillary (upperjaw) sites in the experimental group had calculus while thecorresponding value in the control group was 35 sites. On day 28 thenumber of sites with calculus was 37/48 in the experimental group and40/48 in the control group (see Table 3).

CONCLUSIONS

Adding delmopinol to the tested dog snacks proved to be effective in alldogs. Chewing on the snack alone reduces established gingivitis by 50%but when delmopinol was added in the snack, the reduction was 69% evenin the presence of measurable plague accumulation.

When the pre-experimental oral hygiene measures were stopped, a rapidplaque formation is seen. Within 2 weeks all surfaces exhibit plaque.The use of the snacks, with or without the tested component, did notalter plaque accumulation. However, the bleeding (which is an indicationof the continuous plaque activity) was reduced. Without wishing to bebound by theory, delmopinol appears to reduce plague maturation in sucha way that the plaque that is present stays immature and does notprovoke the inflammatory response that normally leads to gingivitis.Although the inflammation increased in all dogs after stopping thepre-experimental oral hygiene routine, it was significantly less (pairedt-test p=0.05) in the experimental group.

The most prominent effect of the delmopinol dog chew in this study wasseen on calculus formation. Even in the presence of dental plaque andwith a calculus-promoting soft diet, the calculus formation was stronglyreduced in the experimental group. This indicates that the plaque isloosely bound and less densely packed on the tooth surface, which has aneffect on the mineralisation of deposits. When the application ofdelmopinol was stopped, a rapid re-growth of calculus was measurable inall experimental animals, although the measurable visible plaqueaccumulation was unaltered.

This study indicates that administration of delmopinol in a dog snackretards gingivitis formation, reduces established inflammation andinhibits calculus formation.

TABLE 1 Number of sites with presence of dental plaque on the buccalsurfaces of the upper teeth (n = 48) (UJ) and on teeth in the lower jaw(n = 16) (LJ) during the experimental period of 28 days. Day 0 Day 0 Day14 Day 14 Day 28 Day 28 Dog UJ LJ UJ LJ UJ LJ Delmopinol 1 0 4 8 4 12 42 0 4 12 4 12 4 3 0 4 12 4 12 4 4 0 4 6 4 12 4 Sum 0 16 38 16 48 16Control 1 0 4 12 4 12 4 2 0 4 12 4 12 4 3 0 4 12 4 12 4 4 0 4 12 4 12 4Sum 0 16 48 16 48 16

TABLE 2 Number of sites with gingival bleeding at the buccal surfaces ofthe upper teeth (n = 48) (UJ) and at teeth in the lower jaw (LJ) (n =16) during the experimental period of 28 days. Day 0 Day 0 Day 14 Day 14Day 28 Day 28 Dog UJ LJ UJ LJ UJ LJ Delmopinol 1 0 4 3 1 6 3 2 1 4 4 1 72 3 0 4 3 1 4 4 4 0 3 3 2 4 3 Sum 1 15 13 5 21 12 Control 1 0 4 10 2 6 42 0 4 9 2 8 3 3 1 4 7 1 3 4 4 0 4 10 3 9 3 Sum 1 16 36 8 26 14

TABLE 3 Number of teeth with calculus on the buccal surfaces of theteeth in of the upper jaw during the experimental period of 28 days (n =48 measured sites). Dog Day 0 Day 14 Day 28 Delmopinol 1 0 2 8 2 0 4 123 0 0 7 4 0 0 10 Sum 0 6 37 Control 1 0 10 11 2 0 10 12 3 0 12 12 4 0 35 Sum 0 35 40

1-32. (canceled)
 33. A method for treatment of halitosis in a non-humananimal in need thereof which comprises administering a compound ofgeneral formula (I),

wherein R₁ is a straight or branched alkyl group containing 8 to 16carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is astraight or branched alkyl group containing 2 to 10 carbon atoms,substituted with a hydroxy group except in the alpha-position, or apharmaceutically acceptable salt thereof, wherein the compound offormula (I) is coated onto, or infused into, an animal chew.
 34. Themethod according to claim 33, wherein the sum of the carbon atoms in thegroups R₁ and R₂ of the morpholino compound is 10 to
 20. 35. The methodaccording to claim 33 or claim 34, wherein R₂ of the morpholino compoundterminates with the hydroxy group.
 36. The method according to any claim33, wherein the morpholino compound is3-(4-propyl-heptyl)-4-(2-hydroxyethyl) morpholine.
 37. The methodaccording to a claim 33, wherein the chew further comprises anantimicrobial agent.
 38. The method according to claim 33, wherein thechew further comprises a pharmaceutically acceptable excipient.
 39. Themethod according to claim 33, wherein the chew further comprises ananti-inflammatory agent.
 40. The method according to any claim 33,wherein the chew comprises animal hide.
 41. The method according to anyclaim 33, wherein the chew comprises at least one flavouring.
 42. Themethod according to claim 33, wherein the non-human animal is acompanion animal.
 43. The method according to claim 42, wherein thecompanion animal is a dog.
 44. The method according to claim 42, whereinthe companion animal is a cat.